Glycoprotein having inhibitory activity against helicobacter...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai

Reexamination Certificate

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C530S395000, C530S413000, C435S252100, C424S009100

Reexamination Certificate

active

06828298

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a glycoprotein which is capable of eradicating from the stomach
Helicobacter pylori
, which is associated with the occurrence of peptic ulcers. It also relates to an inhibitor of the colonization of
Helicobacter pylori
comprising the glycoprotein, and a medicament and food comprising the inhibitor.
BACKGROUND OF THE INVENTION
At present it is believed that eradication of
H. pylori
from the stomach is essential for fully treating peptic ulcers. The combination of an antibiotic and an inhibitor of gastric acid secretion has been generally proposed as a therapy for eradication of
H. pylori
as described below.
H. pylori
is a gram-negative spiral rod-shaped bacterium having flagella at one end and colonizing the human gastric mucosa. B. J. Marshall and J. R. Warren in Australia reported in 1983 that this bacterium was frequently detected in stomach biopsy specimens from patients with gastritis or gastric ulcers. At that time, this bacterium was named
Campylobacter pylori
since it resembles Campylobacter in morphology and growth characteristics. Later, it was found that the bacterium is different from Campylobacter in the fatty acid composition of its outer membrane and sequence of ribosome 16S-RNA. Therefore, the bacterium is now referred to as
Helicobacter pylori
and belongs to the newly established genus of Helicobacter.
Since then, many reports have been published based on epidemiological studies, indicating that this bacterium causes gastritis, gastric ulcers, and duodenal ulcers and is associated with diseases such as gastric cancer. Once
H. pylori
colonizes gastric mucosa, it survives and persists in the stomach and cannot be eradicated, although the immune response to infection thereof is strong, i.e., the antibody titer is high. Therefore, unless
H. pylori
is completely eliminated from the stomach by antibiotic therapy, the infection will return to the same level as before treatment within about a month after the administration of antibiotics is stopped. Additionally, the pH of the stomach is maintained very low by HCl, which is a strong acid, and therefore most antibiotics tend to be inactivated. For this reason, the combination of an antibiotic and a proton pump inhibitor which strongly suppresses the secretion of gastric acid is utilized for eradication of
H. pylori.
However, the administration of antibiotics for a long time has the serious problems of increasing antibiotic-resistant strains as well as causing side effects.
Japanese Patent Application Kokai No. 11-263731 discloses that milk fat globule membrane fraction is effective for prevention of
H. pylori
infection. However, that publication merely teaches the ability to inhibit haemagglutination of
H. pylori
as evidence of prevention of
H. pylori
infection. Additionally, that publication states that milk fat globule membrane contains various components and does not state that which component is effective. Also, Sun Hirmo et al. states that gastric mucin and milk glycoprotein, specifically far globule membranes prepared from bovine buttermilk inhibit sialic acid-specific haemagglutination of
H. pylori
(FEMS Immunol. Medical Microbiology 20 (1998), pp. 275-281. However, it has been reported that there was no correlation between expression of haemagglutininins by
H. pylori
bacteria and the ability to bind gastric mucosa cells (M. Clyne & B. Drumm, Infection and Immunity, October 1993, pp. 4051-4057. Accordingly, the above-mentioned patent publication and article do not teach or suggest a substance which is capable of inhibiting the adherence of
H. pylori
to gastric mucosa.
Furthermore, the above patent publication and article have not elucidated an adhesin for adherence of
H. pylori
to gastric mucosa and a receptor therefor on gastric mucosa, which are important targets for inhibition of
H. pylori
infection.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide an effective and safe inhibitor of
H. pylori
colonization which is associated with the occurrence of peptic ulcers, which inhibitor is capable of inhibiting the colonization of
H. pylori
effectively without the disadvantages of side effects and increase of drug-resistant strains which are associated with the use of antibiotics, and to provide a medicament and food useful for treating or preventing peptic ulcers.
Other objects and advantages as well as the nature of the present invention will be apparent from the following description.
Generally, the first step for establishment of an infection by a bacterium is adherence of the bacterium to a host cell and colonization of the bacterium by growing there. For the bacterium to adhere to the host cell, an adhesin has to bind to a receptor on the surface of the host cell. The specificity of the infective site of the bacterium is determined by this adhesin and the receptor. If the receptor molecule exists when the bacterium adheres to the host cell, competitive inhibition occurs and an infection is not established.
An adhesin of
H. pylori
and a receptor on human gastric mucosa are thought to be target molecules for inhibition of
H. pylori
infection. The present inventors clarified by studies on the mechanism of adherence of
H. pylori
that the adhesin of
H. pylori
, which had not been elucidated, is urease produced by
H. pylori
(Japanese Patent Application Kokai No. 10-287585).
The present inventors have studied substances capable of inhibiting the adherence of urease to gastric mucosa and have found that glycoproteins such as glycoprotein derived from the milk of a cow or glycoprotein derived from the albumen of a chicken egg are able to eliminate colonized
H. pylori
in the stomach by specifically binding to urease which is an adhesin localized on the surface layer of an
H. pylori
cell, and furthermore have found that the use of glycoprotein capable of specifically binding to urease even in a small amount, which glycoprotein is isolated and purified from these glycoprotein-containing substances by utilization of specific binding to urease, enables remarkably effective elimination of
H. pylori.
According to the present invention, glycoprotein which is capable of specifically binding to urease is isolated and purified from a glycoprotein-containing substance by the affinity column technique which utilizes the specific binding to
H. pylori
urease, and the isolated and purified glycoprotein is used as an inhibitor of
H. pylori
colonization.
In one aspect, the present invention provides a glycoprotein which specifically binds to urease of
Helicobacter pylori
the glycoprotein being obtained by isolation and purification using a method utilizing specific adsorption to
Helicobacter pylori
urease.
In another aspect, the present invention provides an inhibitor of
Helicobacter pylori
colonization, comprising the above-mentioned glycoprotein as an active ingredient. The present invention also provides a pharmaceutical composition suitable for preventing or treating diseases caused by or associated with
Helicobacter pylori
in mammals including humans such as peptic ulcers, comprising the above-mentioned glycoprotein and a pharmaceutically acceptable carrier or diluent. Furthermore, the present invention provides a food which prevents or treats diseases caused by or associated with
Helicobacter pylori
in mammals including humans such as peptic ulcers when consumed in an effective amount, comprising the above-mentioned glycoprotein.
The method utilizing specific adsorption to
Helicobacter pylori
urease used in the present invention is preferably affinity chromatography using a column on which
Helicobacter pylori
urease is immobilized. The urease which is immobilized on the column may be recombinant urease.


REFERENCES:
patent: 5116821 (1992-05-01), Randall et al.
patent: 5505955 (1996-04-01), Peterson et al.
patent: 6235709 (2001-05-01), Kodama et al.
patent: 10-287585 (1998-10-01), None
patent: 11-263731 (1999-09-01), None
Hashimoto et al. (Digestive Disease and Sciences, 36, 888-892 (199

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